miR-200b对克罗恩病肠道上皮-间质转分化及肠壁纤维化的影响及分子机制

One of the most serious complications of Crohn's disease (CD) is intestinal stenosis, which is often resulted from intestinal fibrosis.To our regret, not only do we know little about the mechanisms of the intestinal fibrosis, but also lack effective therapeutic reagents. .From our latest studies, we have noticed that epithelial- mesenchymal transition（EMT）was closely related to the intestinal fibrosis in CD patients. Meanwhile, miR-200b, which was regarded as a main regulator of EMT, is overexpressed in intestinal tissues of CD with complication of fibrosis and inhibited the process of EMT in vitro. According to the microRNA predicting softwares on line, SMAD2 and tissue inhibitor of metalloproteinase 2(TIMP2) are the two main targeted genes of miR-200b,which reminds us that miR-200b may deregulate fibrosis through directly disruptting the signal pathway of intestinal fibrosis. Therefore, we presume that EMT is a main resource of intestinal fibrosis of CD. Furthermore,it is possible that miR-200b inhibit the process of CD fibrosis by regulating both the EMT and fibrosis signal pathway..In future studies, based on the clinical samples and models of CD fibrosis both in vivo and in vitro, we will evaluate the relations among miR-200b, EMT and intestinal fibrosis as well as further study the functions and the corresponding molecular mechanisms of miR-200b in CD fibrosis . We hope that all our efforts will help lay a sound foundation on finding the potential targets to CD fibrosis therapy.

肠壁纤维化是克罗恩病（CD）患者并发肠道狭窄的重要病理原因，其分子机制不明，更缺乏有效治疗手段。本课题组前期研究发现，CD患者肠壁纤维化时伴随上皮-间质转分化（EMT）标志基因表达改变；而作为EMT主要调控分子的miR-200b在CD患者纤维化组织表达增高，并可在体外抑制肠上皮细胞EMT表型转换。生物信息学分析表明miR-200b还可通过靶向调控纤维化基因SMAD2、金属蛋白酶组织抑制因子-2（TIMP-2）而直接抑制纤维化。我们由此推测肠道上皮细胞EMT参与CD肠壁纤维化形成，而miR-200b可调控EMT和肠壁纤维化进程。本项目拟通过临床标本和体内外肠纤维化模型研究，全面评估miR-200b、EMT与CD肠壁纤维化的相关性，观察miR-200b调控EMT和纤维化信号途径对CD肠壁纤维化的影响，从而补充和完善CD肠壁纤维化的分子机制，为寻求潜在分子靶点奠定基础。

肠壁纤维化是克罗恩病（CD）患者并发肠道狭窄的重要病理原因，其分子机制不明，更缺乏有效治疗手段。我们前期研究发现，CD患者肠壁纤维化时伴随上皮-间质转分化（EMT）标志基因表达改变；而作为EMT主要调控分子的miR-200b在CD患者纤维化组织表达增高，并可在体外抑制肠上皮细胞EMT表型转换。生物信息学分析表明miR-200b还可通过靶向调控纤维化基因SMAD2、金属蛋白酶组织抑制因子-2（TIMP-2）而直接抑制纤维化。我们由此推测肠道上皮细胞EMT参与CD肠壁纤维化形成，而miR-200b可调控EMT和肠壁纤维化进程。在本项目资助下，我们通过临床标本和肠纤维化细胞模型研究，全面评估miR-200b、EMT与CD肠壁纤维化的相关性，观察miR-200b调控EMT和纤维化信号途径对CD肠壁纤维化的影响。结果发现：①CD患者发生肠壁纤维化时肠道上皮细胞出现EMT表型改变，与肠壁纤维化密切相关；②TGF-β1可诱导肠上皮细胞出现EMT和纤维化表型，抑制miR-200b表达；③炎症性肠病患者肠粘膜组织中miR-200b表达降低，TGF-β1表达则明显上调；④ miR-200b可抑制TGF-β1诱导的EMT和纤维化表型，其机制可能与miR-200b对SMAD2和ZEB1的调控有关；⑤miR-200b过表达可促进IEC-6细胞增殖，促进细胞周期素cyclin D1的表达。上述研究结果提示，EMT是CD患者纤维化的重要发病机制之一，miR-200b可抑制EMT而对IBD有潜在的治疗价值。